Luigi Puglielli

 

Lipid Signaling in the Aging Brain and Molecular Pathogenesis of Alzheimer's Disease

E-mail: lp1@medicine.wisc.edu

Research Strengths: Molecular Neuroscience, Neurobiology of Disease

Our broad research interests focus on the role that lipid metabolism plays in the regulation of Aβ (amyloid β-peptide) generation and synaptogenesis during both normal aging of the brain and the Alzheimer-type of neurodegeneration. Specifically, we focus on the role played by the ceramide-dependent signaling cascade, and by intracellular cholesterol distribution. Recent work from several groups, including ours, has proved that both ceramide and cholesterol are highly connected to Aβ generation and synaptogenesis, and are regulated in an age-dependent fashion. Our current efforts are focused on the identification of: (i) up-stream and down-stream molecules that mediate the ceramide-dependent regulation of Aβ generation during aging; and (ii) intracellular molecules that can affect APP metabolism and synaptogenesis through intracellular cholesterol dynamics. To address the above questions, we use a combination of biochemical, cellular, and genetic approaches, which normally span from lipid metabolism and trafficking, to signal transduction, ligand-receptor interaction, and post-translational modifications of proteins.

Selected Publications:

• Costantini, C., R.M.K. Kolasani, and L. Puglielli. 2005. Ceramide and cholesterol: Possible connections between normal aging of the brain and Alzheimer’s disease. Just hypotheses or molecular pathways to be identified? Alzheimer’s & Dementia 1: 43-50.
• Puglielli, L., A.L. Friedlich, K.D.R. Setchell, S. Nagano, C. Opazo, R.A. Cherny, K.J. Barnham, J.D. Wade, S. Melov, D.M. Kovacs, and A.I. Bush. 2005. Alzheimer’s Disease b-amyloid activity mimics cholesterol oxidase. J. Clin. Invest. 115: 2556-2563.
• Costantini, C., R. Weindruch, G. Della Valle, and L. Puglielli. 2005. A TrkA to p75NTR molecular switch activates amyloid b-peptide generation during aging. Biochem. J. 391: 59-67.
• Puglielli, L., B.C. Ellis, L.A. Ingano, and D.M. Kovacs. 2004. Role of acyl-coenzyme a: Cholesterol acyltransferase activity in the processing of the amyloid precursor protein. J. Mol. Neurosci. 24: 93-96.
• Hutter-Paier, B., H.J. Huttunen, L. Puglielli, C.B. Eckman, D.Y. Kim, A. Hofmeister, R.D. Moir, S.B. Dominitz, M.P. Frosch, M. Windisch, and D.M. Kovacs. 2004. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 44: 227-238.
• Puglielli, L., R.E. Tanzi, and D.M. Kovacs. 2003. Alzheimer’s disease: The cholesterol connection. Nat. Neurosci. 6: 345-351. [PDF]
• Puglielli, L., B.C. Ellis, A.J. Saunders, and D.M. Kovacs. 2003. Ceramide stabilizes BACE1 and promotes amyloid ß-peptide biogenesis. J. Biol. Chem. 278: 19777-19783. [PDF]
• Puglielli, L., G. Konopka, E. Pack-Chung, L.A. MacKenzie Ingano, O. Berezovska, B.T. Hymam, T.Y. Chang, R.E. Tanzi, and D.M. Kovacs. 2001. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) modulates the generation of the amyloid ß-peptide. Nat. Cell Biol. 3: 905-912. [PDF]